Malaria, a vector-borne infectious disease caused by protozoan parasites, is widespread in tropical and subtropical regions of the world. Each year, there are estimated to be over 500 million cases of malaria, causing the death of between one and three million people. Ninety percent of malaria-related deaths occur in Sub-Saharan Africa, the majority of which are young children. While malaria predominantly effects populations located in Africa and Indonesia, the United States reported 1,337 cases of malaria acquired in malaria-endemic countries, including 8 deaths, in 2001. Even though malaria has been eradicated in the United States since the early 1950's, the two species that were responsible for malaria transmission prior to eradication, Anopheles quadrimaculatus in the east and Anopheles freeborni in the west, are still widely prevalent and present a constant risk that malaria could be reintroduced in the United States. Malaria is contracted when one is bitten by an infective female Anopheles mosquito. Infection occurs when saliva, containing the plasmodium parasite, is transferred during mosquito feeding. Once inside the blood, parasites travel to the liver and multiply. The parasites are released from the liver and back into the bloodstream where they invade the red blood cells and multiply again eventually causing symptoms that include light-headedness, shortness of breath, tachycardia, fever, chills, nausea, flu-like illness, and, in severe cases, coma, and death.
U.S. Pat. No. 4,327,215, J Med Chem 14, 926 (1971) and J Med Chem 17, 210 (1974) describes the synthesis of quinoline derivatives of the following structure:

wherein X and Y can be halogen, methoxy or trifluoromethyl. These compounds are described as anti-malarials and antibacterials being potentially useful for treating a variety of infections including malaria and tuberculosis.
WO 2008/060269 describes quinoline derivatives of the following structure:

wherein the phenyl ring can be substituted by alkyl, Cl, or F and the amino group can be substituted by an alkyl. These compounds are described as anti-malarials.
Mefloquine is an orally-administered and widely used antimalarial drug for prophylaxis against and treatment of malaria. Mefloquine prevents the development of malaria by attacking parasites once they have entered the red blood cells and prevents them from multiplying further. While the exact mechanism of action is unknown, mefloquine is thought to work by blocking the action of a chemical that the parasites produce to protect themselves once inside the red blood cells. The parasites inside the red blood cells digest hemeoglobin. To prevent themselves from being damaged by toxic levels of heme, the malaria parasites produce a chemical that converts heme into a compound that is nontoxic. Mefloquine is believed to blocks this process.
In addition to its efficacy against plasmodium falciparum, mefloquine has also been reported to have activity against mycobacterium tuberculosos (TB) [Antimicrob. Agents Chemother., 2000, 44, 848; Antimicrob, Agents Chemother., 1999, 43, 1870; Antimicrob, Agents Chemother., 2004, 48, 3556] as well as, antimicrobial, antiprotozoan, antibacterial and anti fungal activity.
In addition to acting in the periphery to treat malaria, mefloquine also crosses the blood-brain barrier (BBB), producing a spectrum of psychiatric and neurological disorders, including hallucinations, delusional thinking, convulsions, depression, anxiety, paranoia, aggression, nightmares, insomnia, peripheral motor-sensory neuropathy, vestibular (balance) damage, suicidal ideation and symptoms of traumatic brain injury. The incidence and severity of adverse psychiatric side effects has limited the use of this otherwise best in class antimalarial agent.
It is well known that binding to non-targeted receptors in brain can often lead to unwanted psychiatric and neurological side effects of non-Central Nervous System (CNS) drugs [Endocrine Reviews 2006, 27: 73]. Access to the CNS is neither associated with nor necessary for mefloqine efficacy against parasites and/or other infections. Reducing or eliminating the ability of mefloquine to cross the BBB, or otherwise reducing brain levels sufficient to prevent psychiatric and neurological side effects, while retaining antimalarial and other therapeutic efficacy, would result in a safer therapy. The need for new agents with greater safety and high therapeutic effectiveness, coupled with the emerging resistance strains to current treatments has created an urgent unmet medical need. There is, therefore, a real and continuing necessity for the development of improved medications that treat or prevent malaria.
In view of the above, it is highly desirable to find effective and highly selective anti-malarials with limited or no CNS adverse side effects, including hallucinations, delusional thinking, convulsions, depression, anxiety, paranoia, aggression, nightmares, insomnia, peripheral motor-sensory neuropathy, vestibular (balance) damage, suicidal ideation and symptoms of traumatic brain injury. In particular, it is desirable to find compounds that exert their antimalarial action in peripheral tissues (e.g., blood and liver), while not entering in brain. In this way, peripherally-mediated beneficial effects of anti-malarial agents should be maintained, whereas CNS side effects should be reduced or eliminated. This should provide a novel opportunity to develop safer alternatives to highly brain penetrant anti-malarial agents for the prevention or treatment of malaria and other infectious diseases (e.g., tuberculosis).